According to the American Heart Association, an estimated 100,870,000 American adults have total cholesterol levels in the borderline-high risk range of 200 mg/dl to 239 mg/dl, and there are 40,600,000 American adults living with high-risk cholesterol levels of 240 mg/dl or more. There are many risk factors that can indicate a propensity to have high levels of cholesterol, such as age, weight, and health conditions such as diabetes, smoking, gender, race and ethnicity.
Hypercholesterolemia, or elevated blood cholesterol levels due to concentration of cholesterol in the cells and plasma, is an important risk factor definitively connected with potentially deadly cardiovascular disease, including atherosclerosis, coronary artery insufficiency, coronary heart disease, myocardial infarction and stroke. Millions of people around the world suffer from coronary heart disease, and it is the leading cause of death and morbidity at a productive age, especially in Western Europe and in the United States. Accordingly, cardiovascular disease presents a significant drain on healthcare resources in the western world. In the United States, total costs (direct and indirect) connected with the disease were estimated as about $118 billion in 2000; for 1.1 million citizens that experienced myocardial infarction, more than 40% of those died [Terry A. Jacobson, Clinical Context: Current Concepts of Coronary Heart Disease Management, Am J. Med. 2001; 110 (6A):3S-11S]. In addition, cardiovascular disease is growing at an alarming rate in Asian countries, and in particular among Asian Indians where cardiovascular disease has reached epidemic proportions [1].
Cholesterol (and its derivatives) biosynthesis underlies cardiovascular disease and, accordingly, inhibitors of cholesterol biosynthesis are a major focus of research efforts towards new therapeutics for cardiovascular disease. For a number of years, significant research was aimed at the development of competitive inhibitors for 3-hydroxy-3-methylglutaryl coenzyme A reductase, a major regulatory enzyme of cholesterol biosynthesis. Many attempts to use for this purpose oxygenated sterols, which via binding oxysterol receptors were expected to decrease activity of HMG-CoA reductase, did not bring practical results. A series of fungal metabolites with very high affinities for HMG-CoA reductase were found to be highly efficient inhibitors of cholesterol biosynthesis. These compounds and some synthetic analogs are commonly known as statins, are available commercially, and are widely used.
Although being relatively safe and efficient in treatment and prevention of coronary heart disease, statins have certain limitations in their use because of possible deleterious side effects, such as muscle weakness, and renal failure. Statin therapy is contra-indicated in pregnant women and patients with liver disorders. Additionally, there is a significant patient population in whom statins are not effective, and so the need for an agent that will lower cholesterol extends beyond the number of patients currently taking statins to lower their cholesterol levels. Taking additionally into account the relatively high costs of statin therapy, which varies from $20,000 to $40,000 per quality-adjusted life-year saved [John A. Farmer, Economic Implications of Lipid-Lowering Trials: Current Considerations in Selecting a Statin, Am J Cardiol 1998; 82:26 M-31M], and the desirability of long-term permanent treatment [Terry A. Jacobson, Clinical Context: Current Concepts of Coronary Heart Disease Management, Am J Med. 2001; 110 (6A):3S-11S], it is evident that new agents are needed with similar targeting as the statins but with higher potency, safety, and availability and that will provide significant cost savings.
Accordingly, the instant invention provides novel compounds with anticholesterolemic activity, and methods of use.